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Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Wildschut, Mattheus H E ; Mena, Julien ; Dördelmann, Cyril ; van Oostrum, Marc ; Hale, Benjamin D ; Settelmeier, Jens ; Festl, Yasmin ; Lysenko, Veronika ; Schürch, Patrick M ; Ring, Alexander ; Severin, Yannik ; Bader, Michael S ; Pedrioli, Patrick G A ; Goetze, Sandra ; van Drogen, Audrey ; Balabanov, Stefan ; Skoda, Radek C ; Lopes, Massimo ; Wollscheid, Bernd ; Theocharides, Alexandre P A ; Snijder, Berend

Nature Publishing Group 2023-10

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  • Título:
    Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
  • Autor: Wildschut, Mattheus H E ; Mena, Julien ; Dördelmann, Cyril ; van Oostrum, Marc ; Hale, Benjamin D ; Settelmeier, Jens ; Festl, Yasmin ; Lysenko, Veronika ; Schürch, Patrick M ; Ring, Alexander ; Severin, Yannik ; Bader, Michael S ; Pedrioli, Patrick G A ; Goetze, Sandra ; van Drogen, Audrey ; Balabanov, Stefan ; Skoda, Radek C ; Lopes, Massimo ; Wollscheid, Bernd ; Theocharides, Alexandre P A ; Snijder, Berend
  • Assuntos: biology ; Clinic for Oncology and Hematology ; Institute of Molecular Cancer Research ; Life sciences ; Medicine & health
  • Notas: Wildschut, Mattheus H E; Mena, Julien; Dördelmann, Cyril; van Oostrum, Marc; Hale, Benjamin D; Settelmeier, Jens; Festl, Yasmin; Lysenko, Veronika; Schürch, Patrick M; Ring, Alexander; Severin, Yannik; Bader, Michael S; Pedrioli, Patrick G A; Goetze, Sandra; van Drogen, Audrey; Balabanov, Stefan; Skoda, Radek C; Lopes, Massimo; Wollscheid, Bernd; Theocharides, Alexandre P A; Snijder, Berend (2023). Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis. Nature Communications, 14(1):6414.
    https://www.zora.uzh.ch/id/eprint/238390/
    PMCID: PMC10570306
    10.1038/s41467-023-42101-z
  • Descrição: Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
  • Editor: Nature Publishing Group
  • Data de criação/publicação: 2023-10
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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